Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis

Area of Science:

• Cardiovascular Biology
• Fibrosis Research
• Cellular Origins

Background:

• Cardiac fibroblasts drive heart failure progression through extracellular matrix deposition.
• Endothelial-to-mesenchymal transition (EndoMT) and hematopoietic progenitors were considered primary sources of cardiac fibroblasts post-injury.
• Identifying the precise origins of cardiac fibroblasts is crucial for developing effective heart failure therapies.

Purpose of the Study:

• To investigate the cellular origins of cardiac fibroblasts following pressure overload-induced cardiac injury.
• To determine if EndoMT or hematopoietic cells contribute to the fibroblast population expansion.
• To identify resident fibroblast lineages involved in cardiac fibrosis.

Main Methods:

• Utilized multiple independent murine Cre lines for genetic lineage tracing.
• Employed a collagen1a1-GFP fusion reporter to specifically label and track fibroblasts.
• Induced cardiac pressure overload in mouse models to mimic injury conditions.

Main Results:

• Cardiac fibroblasts following pressure overload were not derived from hematopoietic cells, EndoMT, or epicardial-to-mesenchymal transition.
• Pressure overload stimulated comparable proliferation and activation of two resident fibroblast populations.
• One identified fibroblast population was of epicardial origin, and the other was of endothelial origin.

Conclusions:

• Cardiac fibroblasts in pressure overload models arise from resident lineages, not EndoMT or infiltrating cells.
• These findings challenge current therapeutic strategies targeting EndoMT or hematopoietic cells.
• Future therapies should focus on common pathways regulating endogenous fibroblast populations to treat cardiac fibrosis and heart failure.